Predicting Response and Recognizing Resistance: Improving Outcomes in Patients With Castration-resistant Prostate Cancer - 01/11/17

Doi : 10.1016/j.urology.2017.04.062

Neal Shore ^a,^* , Axel Heidenreich ^b, Fred Saad ^c
^a Carolina Urologic Research Center, Myrtle Beach, SC
^b Department of Urology, Uro-Oncology, Robot-assisted and Reconstructive Urological Surgery, University Hospital of Cologne, Cologne, Germany
^c Department of Urology, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada

^*Address correspondence to: Neal Shore, M.D., Carolina Urologic Research Center, 823 82nd Parkway, Myrtle Beach, SC 29572.Carolina Urologic Research Center823 82nd ParkwayMyrtle BeachSC29572

Abstract

Optimal sequencing strategies for approved agents in metastatic castration-resistant prostate cancer (mCRPC) are unclear. Retrospective clinical studies suggest cross-resistance between specific therapies. This review assesses treatment decisions for mCRPC. Increased use of chemohormonal therapy in castration-sensitive disease may affect subsequent treatment decisions in mCRPC. Initial abiraterone or enzalutamide treatment may result in cross-resistance for subsequent androgen receptor-targeted therapy. Clinical responses may be seen in both docetaxel- and cabazitaxel-treated patients progressing after treatment with abiraterone or enzalutamide. These observations are supported by proposed resistance mechanisms. In conclusion, small, retrospective studies suggest cross-resistance between specific therapies in mCRPC. Larger prospective studies are required.

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Plan

Current Treatment Options for mCRPC

Chemotherapy in Castration-sensitive Disease

Treatment Sequencing and Clinical Cross-resistance in mCRPC

Prior Treatment Effect on Abiraterone Efficacy

Prior Treatment Effect on Enzalutamide Efficacy

Prior Treatment Effect on Docetaxel Efficacy

Prior Treatment Effect on Cabazitaxel Efficacy

Sipuleucel-T and Radium-223

Mechanisms of Resistance to AR-targeted Agents

AR Splice Variants

AR Mutations

AR Gene Amplification

CYP17A1 Upregulation and De Novo Steroidogenesis

Upregulated Glucocorticoid Receptor (GR) Signaling

ERG Rearrangements

Additional Mechanisms

Mechanisms of Resistance to Chemotherapy

AR Splice Variants

Tubulin Alterations

ERG-Tubulin Interactions

Multidrug Resistance

ADT-induced Resistance to Chemotherapy

Additional Mechanisms

Indicators of Therapeutic Resistance in mCRPC

Financial Disclosure: Paul Scutt, MediTech Media, provided medical writing services supported by Sanofi Genzyme. Neal Shore has served as a consultant for and has obtained research funding from Astellas, Bayer, Abbvie, Amgen, Ferring, Janssen, Medivation, and Sanofi Genzyme. Axel Heidenreich has served as a consultant for Astellas, Amgen, Ferring, Ipsen, Janssen Cilag, Pfizer, Sanofi, and Takeda, and has received research funding from Astellas and Sanofi. Fred Saad has served as a consultant for and has obtained research funding from Astellas, Janssen, Sanofi, and Bayer.